What is the recommended dosage and usage of Atovaquone (generic name) for treating Pneumocystis jirovecii pneumonia and malaria?

Atovaquone Dosing and Usage

Atovaquone is FDA-approved for prevention and treatment of mild-to-moderate Pneumocystis jirovecii pneumonia (PCP) in patients who cannot tolerate trimethoprim-sulfamethoxazole, and is also used for malaria treatment, but it is NOT appropriate for severe PCP. 1

FDA-Approved Dosing for PCP

Prevention of PCP

• 1,500 mg (10 mL) once daily with food 1
• Indicated for adults and adolescents ≥13 years who cannot tolerate TMP-SMX 1

Treatment of Mild-to-Moderate PCP

• 750 mg (5 mL) twice daily with food for 21 days (total daily dose = 1,500 mg) 1
• Only for mild-to-moderate disease (alveolar-arterial oxygen gradient ≤45 mm Hg) 1
• Contraindicated for severe PCP (A-a gradient >45 mm Hg) - use clindamycin plus primaquine instead 2, 1

Pediatric Dosing (from guidelines, not FDA label)

• Children and adolescents: 30-40 mg/kg/day in 2 divided doses with fatty foods 3
• Infants 3-24 months: 45 mg/kg/day (higher dose required due to different pharmacokinetics) 3, 4

Critical Administration Requirements

Must Take With Food

• Always administer with food, particularly high-fat meals 1
• Food increases bioavailability 1.4-fold compared to fasting state 3, 4
• Failure to take with food results in lower plasma concentrations and treatment failure 1
• Shake suspension gently before administering 1

When NOT to Use Atovaquone

• Severe PCP (PaO₂ <70 mm Hg or A-a gradient >35-45 mm Hg) - use TMP-SMX or clindamycin-primaquine instead 2, 1
• Patients with malabsorption or chronic diarrhea (associated with lower drug levels, therapeutic failure, and death) 5, 4
• Patients who cannot reliably take medication with food 4
• Patients failing TMP-SMX therapy (efficacy not established) 1

Malaria Treatment Dosing

Uncomplicated Malaria (Chloroquine-Resistant Areas)

Atovaquone-proguanil (Malarone) combination: 3

• 5-8 kg: 2 pediatric tablets × 3 days 3
• 9-10 kg: 3 pediatric tablets × 3 days 3
• 11-20 kg: 4 pediatric tablets or 1 adult tablet × 3 days 3
• 21-30 kg: 2 adult tablets × 3 days 3
• 31-40 kg: 3 adult tablets × 3 days 3
• >40 kg: 4 adult tablets × 3 days 3

Pediatric tablets contain 62.5 mg atovaquone/25 mg proguanil; adult tablets contain 250 mg atovaquone/100 mg proguanil 3

Drug Interactions

Medications That DECREASE Atovaquone Levels

• Rifampin, rifabutin (avoid combination) 3, 4
• Acyclovir, opiates, cephalosporins, benzodiazepines 3, 4

Medications That INCREASE Atovaquone Levels

• Fluconazole and prednisone 3, 4

Adverse Effects

• Rash (10-15%) - most common, usually occurs after first week 3
• Nausea and diarrhea 3
• Elevated liver enzymes 3
• Hepatotoxicity - rare cases of cholestatic hepatitis and fatal liver failure reported 1
• Treatment-limiting adverse effects occur in only 7-9% of patients (significantly lower than TMP-SMX at 20-24%) 5, 6

Efficacy Considerations

Comparative Effectiveness

• Less effective than TMP-SMX for PCP treatment (20% failure rate vs 7% with TMP-SMX) 5
• Better tolerated than TMP-SMX with fewer treatment-limiting side effects 5, 6
• As effective as pentamidine for mild-to-moderate PCP 7
• Higher mortality within 4 weeks of treatment completion compared to TMP-SMX (11 deaths vs 1 death in pivotal trial) 5

Position in Treatment Algorithm

For PCP treatment: 3, 2

1. First-line: TMP-SMX (15-20 mg/kg/day of TMP component)
2. First alternative for severe disease: Clindamycin plus primaquine
3. Alternative for mild-moderate disease: Atovaquone (if TMP-SMX intolerant and disease not severe)
4. Alternative: Pentamidine IV (for TMP-SMX failure or intolerance)

For PCP prophylaxis: 3

1. First-line: TMP-SMX (1 DS daily or 3x/week)
2. Alternatives: Dapsone, aerosolized pentamidine, or atovaquone 1,500 mg daily

Common Pitfalls to Avoid

• Do not use atovaquone for severe PCP - it has only been studied in mild-to-moderate disease and is associated with higher mortality 1, 5, 8
• Do not prescribe without emphasizing food requirement - absorption is profoundly food-dependent and failure to take with food causes treatment failure 1, 5
• Do not use in patients with diarrhea or malabsorption - associated with lower drug levels, therapeutic failure, and death 5, 4
• Do not combine with rifampin or rifabutin - significantly decreases atovaquone levels 3, 4
• Monitor liver function in patients with hepatic impairment - cases of fatal liver failure reported 1